Biocompatible, biodegradable polymers have been widely used in the medical field as surgical sutures, tissue regenerative induction membranes, protective membranes for the treatment of wounds, and drug delivery systems Among biodegradable polymers, polylactide (PLA), polyglycolide (PGA) and a copolymer (PLGA) of lactide and glycolide have been the subject of many studies and are commercially available since they have good biocompatibility and are decomposable in the body to harmless materials such as carbon dioxide, water, etc.
One example of a biodegradable polymeric drug delivery system is a system wherein a drug is contained in a biodegradable polymer matrix which has the disadvantage of having to be implanted via surgery. In the form of injectable drug delivery systems, polymeric microspheres and nanospheres are known in the art. However, those systems have disadvantages in that they require special preparation methods. In addition, since the biodegradable polymers used can only be dissolved in organic solvents preparation requires the use of organic solvents harmful to the human body and therefore any residual solvent remaining after preparation of the microspheres must be completely removed. Furthermore, some drugs such as polypeptides and proteins may lose their physiological activity after contacting organic solvents.
U.S. Pat. No. 5,384,333 discloses an injectable drug delivery composition in which a pharmacologically active substance is contained in a copolymer comprising a hydrophilic part and a hydrophobic part. The composition is in a solid state at temperatures ranging from 20° C. to 37° C. and is in a fluid state at temperatures ranging from 38° C. to 52° C. The composition has to be heated to a relatively high temperature such as 38° C. to 52° C., immediately before use and it is difficult to uniformly distribute the drug in the polymeric composition.
U.S. Pat. No. 5,612,052 discloses a block copolymer composition characterized by a hydrophobic polyester (A) and a hydrophilic polyethylene oxide (B) which are combined in the form of an A-B-A triblock, which is then hydrated by contacting it with water which then forms a hydrogel However, the drug incorporated in this composition is rapidly released and therefore a special means of using separate biodegradable fine particles containing the drug, in the form of a suspension, is required.
U.S. Pat. No. 5,702,717 discloses a system for delivery of proteins containing A-B-A type block copolymers comprising hydrophobic biodegradable polyesters (A) and hydrophilic polymeric polyethylene oxide (B), which undergo sol-gel phase transition in an aqueous solution at particular temperatures and concentrations. This system takes advantage of a thermal property of the block copolymers in that they are dissolved in water at temperatures below 20° C. and undergo phase transition to form a gel at temperatures above about 30° C. Thus, this system uses a composition in which the drug is dissolved together with the polymers in an aqueous solution at low temperatures, the resulting solution is then injected into a human body via a syringe. At body temperature the polymers undergo phase transition to form a gel and then the drugs incorporated therein is slowly released. Since the polymers are biodegradable, the preparation of this composition does not require the use of organic solvents or any special methods and the composition can be simply sterilized by using a membrane filter. However, this method has several drawbacks in that since the constituents of the block copolymers are degradable polymers and can be hydrolyzed with water, they cannot be commercialized in the form of a polymeric aqueous solution. In addition, since the composition needs to be dissolved in water before use which requires more than half an hour, it is difficult for this composition to be converted into a commercial product. Furthermore, since water is the main constituent, although it is suitable as a delivery system for the long term administration of peptide or protein medicines and drugs which are sparingly soluble in water, it is not a suitable composition to be used as a biodegradable implant since aqueous mono-molecular medicines are rapidly released over short periods of time.
U.S. Pat. No. 5,599,552 discloses a composition wherein a water-insoluble biodegradable thermoplastic polymer is dissolved in a water-miscible organic solvent, and the resulting composition can be implanted where it then undergoes a phase transition when in contact with water or body fluids. However, the drawback is that it is difficult to use because a mono-molecular organic solvent is used to dissolve the biodegradable thermoplastic polymer. Most mono-organic solvents, such as N-methyl-2-pyrrolidone, ethyl lactate, dimethylsulfoxide, etc., cause side effects such as cell dehydration and tissue necrosis, etc. and they may also cause severe pain at the application sites.
U.S. Pat. No. 5,607,686 discloses a liquid polymeric composition prepared by mixing a hydrophilic liquid polymer, instead of a mono-molecular organic solvent, with a water-insoluble hydrophobic polymer. When contacted with water the composition undergoes a phase transition and forms an implant and thus it does not cause a the rapid volume reduction and it has no special side effects due to the good cyto-compatibility of the low molecular weight polyethylene oxide. However, the water-insoluble hydrophobic polymers used are not biodegradable. In addition, the preparation of the composition requires heating to about 80° C. in order to achieve uniform mixing of the water-insoluble hydrophobic polymer and the hydrophilic liquid polymer. Therefore, this system may be suitable to use for adherence prevention and wound protection without any physiologically active substance, but it is not suitable for delivery of physiologically active substances, particularly peptide or protein medicines because peptide and protein medicines lose their activities at high temperatures. Furthermore, protein medicines are water soluble, thus it is very difficult to uniformly incorporate them into the composition. In addition, it is not disclosed in this patent how the drugs or physiologically active substances can be uniformly incorporated in the polymeric composition. Particularly, although polylactide, polyglycolide and their copolymers can be mixed with polyethylene glycol at high temperatures of 80° C. in order to obtain a uniform composition, the composition undergoes phase separation when it stands for a long period of time due to the lowered affinity of the polylactide, the polyglycolide or their copolymers with polyethylene glycol. Therefore, it is very difficult to maintain a uniform composition.
Sterilization steps are necessary in the preparation of implant formulations. Existing sterilization methods are unsuitable for implant formulations due to properties of the implant compositions or because the methods are uneconomical or too complicated. For example, it is almost impossible to prepare a uniform solution by mixing a drug, a water-insoluble biodegradable polymer and a hydrophilic polymer. Therefore, the composition cannot be sterilized by simple methods such as membrane filtration, and must be sterilized by radiation exposure or EO (ethylene oxide) gas methods. However, radiation may cause damage to the drug and the EO gas method is pharmaceutically unacceptable as a method to sterilize the implant formulation. Furthermore, although the formulation may be prepared under sterilized conditions, such methods are very expensive to the extent that the practicability of the preparation may be lowered. Thus, a composition for use as an implant which can be prepared by a simple procedure, and which releases the drug over a long period and which is administered by a single injection and which can decompose into materials harmless to human body is needed.